The cornea focuses light on the retina, providing more than two thirds the refractive power of the eye. To perform this function, it must be completely transparent, and it must have a precise shape, achieved during embryonic development. The adult cornea appears to have multiple mechanisms for leaving a good thing well enough alone, a group of phenomena we defined in the current project period as "corneal constancy". When damage to the cornea is extensive enough, corneal constancy can be overcome, and a repair response ensues. The quality of repair in the cornea exists on a spectrum, with the process at one end being almost completely regenerative while at the opposite end is fibrotic repair. In the cornea, fibrosis creates opacity, and the contraction of fibrotic repair tissue alters corneal shape. These effects impinge undesirably on the capacity to refract light on the retina. The long-term goal of this project is to improve our understanding of corneal stasis, the repair response, and the mechanisms that confer regenerative character. Over the past decade, this research group and others have developed a model for fibrotic progression as a two step process that begins when keratocytes are "activated", assuming a "fibroblast" phenotype, which can progress to the "myofibroblast" phenotype associated with fibrotic repair. Insight has also been acquired into some of the molecular mechanisms determining activation and progression. Moreover, this lab group has identified important differences between corneal repair and repair in vascularized tissues. In the new project period, the group proposes to follow up on some of these key findings with the goal of clinical application. The two aims address the following: 1) keratocyte activation and the mechanisms for loss of the corneal crystalline transketolase, important for cell transparency;2) transition to fibrosis and the mechanism whereby the corneal epithelial basement membrane determines release of the fibrotic regulator TGF-beta2. At the present time, corneal refractive correction revolves around the increasing refinement of surgical technique to limit the quantity of the wound repair response. However, it could be argued that surgical outcomes might also be improved by controlling the quality of repair. The group will focus on questions that promise to provide new insight into molecular targets for pharmacologic intervention.